Pharmaceutical compositions comprising 3-(5-nitro-2-imidazolyl-methylen-amino)-2-oxazolidinones and their use in trichomoniasia

ABSTRACT

1. A PHARMACEUTICAL COMPOSITION CONTAINING, IN ADMIXTURE WITH A PHARMACEUTICALLY ACCEPTABLE CARRIER, A TRICHOMONACIDALLY EFFECTIVE AMOUNT OF A 3-(5-NITRO-2IMIDAZOLYLMETHYLENAMINO) - 2 - OXAZOLIDINONE OF THE FORMULA   2-(O=),3-((1-X,5-(O2N-)IMIDAZOL-2-YL)-CH=N-),5-(R-CH2-)-   OXAZOLIDINE   WHEREIN X IS ALKYL OR ALKENYL OF 1-5 CARBON ATOMS OR ALKYL OF 2-5 CARBON ATOMS SUBSTITUTED AT THE 2-POSITION BY HYDROXY, ALKANOYLOXY OF 1-5 CARBON ATOMS OR BENZOYLOXY; AND R IS S-A, SO2-A OR   -N(-R1)-R2   WHREIN A IS ALKYL OF 1-10 CARBON ATOMS AND R1 AND R2 ARE EACH ALKYL OF 1-5 CARBON ATOMS, PHENYL OR BENZYL OR, COLLECTIVELY WITH THE N-ATOM A PYRROLIDINO, PIPERIDINO, HOMOPIPERIDINO, MORPHOLINO, PIPERAZINO OR A CORRESPONDING RING SUBSTITUTED BY ALKYL OF 1-5 CARBON ATOMS, OR A PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALT THEREOF.

United States Patent 015cc PHARMACEUTICAL COMPOSITIONS COMPRISING 3(S-NITRO 2 IMIDAZOLYL-METHYLEN- AMINO)-2-0XAZOLIDINONES AND THEIR USE INTRICHOMONIASIA Clemens Rufer, Eberhard Schroder, and Hans-JoachimKessler, Berlin, Germany, assignors to Schering Aktiengesellschaft,Mullerstr, Germany No Drawing. Continuation-impart of application Ser.No. 29,236, Apr. 16, 1970, now Patent No. 3,752,809. This applicationApr. 18, 1973, Ser. No. 352,310

Claims priority, application Germany, Apr. 17, 1969, P 19 20 150.4 Int.Cl. A61k 27/00 US. Cl. 424-248 23 Claims ABSTRACT OF THE DISCLOSUREPharmaceutical compositions comprising 3-(5-nitro-2- imidazolylmethylenamino)-2-oxazolidinones of the formula I F I I on,-R OZNLiCH=N-N o N group are useful in the treatment of Trichomonas vaginalis.

BACKGROUND OF THE INVENTION This is a continuation-in-part ofapplication Ser. No. 29,236, filed Apr. 16, 1970.

The eifectiveness of nitroimidazoles against trichlomonads has beenknown since the discovery of the antibiotic azamycin (2-nitroimidazole,S. Nakamura and H. Umezawa, I. Antibiotics (Tokyo), 9 A 66 [1955]).These and other Z-nitroimidazoles, however, did not prove to be betterthan metronidazole (see below) G. C. Lancini, E. Lazzari, R. Pallanea,I1 Farmaco Ed Sc. 21, 278 [1966]), and the ED and LD values wereconsiderably less favorable (E. Grunberg, E. Titsworth, AntimicrobialAgents and Chemotherapy 1965, 1966, 478). Of the S-nitroimidazoles, onlythe commercial preparation metronidazole (S-nitro 2methyl-1-(2-hydroxyethyl)- imidazole), with a minimum inhibitoryconcentration of 2.5 7/ ml. against Trichomonas vaginalis, evolved asthe best of a large number of synthesized compounds. See C. Cosar,Arzneimittelforschung, 16, 23 (1966); also, inter alia, French Pat.1,212,028.

Nitroimidazoles carrying, like the conventional antibacterialnitrofurans, a functionalized carbon atom in the 2-position, such as,for example, an aldehyde, carboxyl, or nitrile group, are known fromAustralian application 55580/65 and Dutch application 64/09120. In theAustralian application are also described, inter alia, the functionalderivatives of the 2-aldehydes, e.g., semicarbazones, hydrazones, etc.,and the antitrichomonal activity is emphasized. Minimum inhibitoryconcentrations of such compounds are not reported.

3,839,567 Patented Oct. 1, 1974 SUMMARY OF THE INVENTION Thepharmaceutical compositions of this invention comprise, in admixturewith a pharmaceutically acceptable carrier, a3-(5-nitro-2-imidazolyl'methylenamino)-2-oxazolidinone of the formula:

ii wherein X is a saturated or unsaturated hydrocarbon group of 1-5carbon atoms, which is unsubstituted or substituted in the 2-position byhydroxy, acyloxy of 1-5 carbon atoms or benzoyloxy, and R is the groupS-A, SOA, SO A or R1 N/ Rz wherein A is a saturated or unsaturatedhydrocarbon group containing 1-10 carbon atoms and R and R which can bethe same or diiferent, are saturated or unsaturated hydrocarbon groupsof 1-5 carbon atoms, a carbocyclic aryl group, e.g., a phenyl or benzylor, together with the amino nitrogen atom, a heterocyclic aminosubstituent containing, e.g., 3 to 14, preferably 5 or 6 ring atoms, 1to 3 rings and 0 to 2 additional ring heteroatoms selected from thegroup consisting of 1 to 2 nitrogen, 1 oxygen and 1 sulfur atom, and isunsubstituted or substituted by 1, 2 or more alkyl of 1 to 5 carbonatoms, and contain l-2 N-, O- or S-atom in addition to the aminonitrogen atom as a ring member, both in free base form and in the formof their physiologically acceptable acid addition salts. In its methodof use aspect, this invention relates to the treatment of trichomoniasisby administering to the infected patient an effective amount of acomposition of this invention.

DETAILED DISCUSSION Examples of A and X which are saturated hydrocarbonare methyl, ethyl, isopropyl, butyl, sec-butyl, isobutyl, tert.-butyl,hexyl, heptyl, octyl, nonyl and decyl. Examples of unsaturatedhydrocarbon are alkenyl and alkynyl of 1-8 carbon atoms, e.g., ethenyl,ethynyl, allyl, propynyl, l-methylallyl, crotyl, butadienyl, 2-octenyl,6- octenyl, etc. Preferred are those of 1-4 carbon atoms with a singleunsaturation, preferably an ethylenic double bond in the B-position.Examples of substituted hydrocarbon are alkyl of 1-4 carbon atomssubstituted by hydroxy, chloro, bromo, acyloxy or alkoxy of 1-8 carbonatoms, e.g., hydroxyethyl, y-hydroxypropyl, acyloxyalkyl wherein alkylpreferably is ethyl and acyloxy preferably is alkanoyl of 15 carbonatoms, or benzoyl. Examples of S-A, SOA and S0 "-A are methylthio,ethylthio, isopropylthio, butylthio, hexylthio, octylthio,methylsulfoxide, ethylsulfoxide, isopropylsulfoxide, butylsulfoxide,hexylsulfoxide, methylsulfonyl, ethylsulfonyl, etc.

Specific examples of compounds of the formula I in which R is the groupSOA are 3-(5-nitro-l-methyl-2- 3 imidazolyl-methylenamino) 5isopropyl-thiomethyl-Z- oxazolidinone-S-oxide azolyl-methylenamino) 5butylthiomethyl-Z-oxazolidinone-S-oxide, which S-oxide compounds areproduced by oxidizing the corresponding thio compounds under mildconditions, e.g., with a molar equivalent of hydrogen perOxide at C. orcolder to avoid oxidation to the corresponding sulfone.

Specific examples of other compounds in addition to those of theexamples which follow are 3- (S-nitro-1-allyl-2-imidazolyl-methylenamino morpholinomethyl-2-oxazolidinone,

3- [5-nitro-1-(2-butenyl) -2-imidazolyl-methylenamino]-5-morpholinomethyl-2-oxazolidinone,

3- 5 -nitro-1 -B-hydroxyethyl-2-imidazolyl-methylenamino)-5-morpholinomethyl-2-oxazolidinone,

3- 5 -nitrol -5-acetoxyethyl-Z-imidazolyl-methylenamino)-5-morpholinomethyl-2-oxazolidinone,

3-(5-nitro-1-;9-benzoyloxylethyl-Z-imidazolyl-methylenamino-5-morpholinomethyl-Z-oxazolidinone,

3 -(S-nitro-1-cyclopentyl-Z-imidazolyl-methylenarnino)-5-morpholinomethyl-Z-oxazolidinone,

3- (S-nitrol-methyl-2-imidazolyl-methylenamino -5-thiomorpholinomethyl-2-oxazolidinone,

3- (S-nitrol-methyl-Z-imidazolyl-methylenamino-5- vindolinomethyl-2-oxazolidinone,

3-(S-nitro-1-methyl-2-imidazolyl-methylenamino)-5-isoindolino-methyl-2-oxazolidinone,

3- S-nitro- 1-methyl-2-imidazolyl-methylenamino -5-imidazolinornethyl-Z-oxazolidinone,

3- S-nitro- 1-methyl-2-imidazolyl-methylenamino -5-tetrahydroxazolinomethyl-2-oxazolidinone,

3-(S-nitro-1-methyl-2-imidaz0lyl-methylenamino)-5-hexahydropyrimidinomethyl-Z-oxazolidinone,

etc.

Other examples of compounds of this invention are those having one ormore, usually not more than four and preferably not more than three,simple substituents on the X group, e.g., chloro and fluoro,lower-alkyl, including methyl, ethyl, propyl and octyl, trifluoromethyl,trichloromethyl, lower-alkoxy, including methoxy and ethoxy, aryloxy,and aralkoxy, including 'benzyloxy and phenoxy, hydroxy, carboxy, nitro,sulfato, acetamido, aryl, including phenyl and aralkyl, includingbenzyl.

Preferably, so that the activity and characteristic structure ispredominantly that of a3-(5-nitro-2-imidazolylmethylenamino)-5-substituted-Z-oxazolidinone, thesum of the molecular weight of these substituents is less than the sumof the molecular weights of the imidazole and its 2-positionsubstituent, e.g., less than 200 and more preferably less than 150, andpreferably less than 8 carbon atoms and less than 4 heteroatoms.

Although the compounds of this invention in which X is an acyloxyalkylgroup are preferably those of Formula I wherein the acyloxy group islower-alkanoyloxy or benzoyloxy, this invention also relates tocompounds of Formula I in which X is an esterified hydroxy-alkyl groupin which the acyloxy group contains 1 to 14, preferably 1 to 7 carbonatoms and 0 to 4, preferably 0 to 1, rings and 0 to 3, preferably 0 to2, heteroatoms. Examples of esterified hydroxy groups are acyloxy groupswherein the acyl group is the acyl radical of, for example, an aryl oralkaryl acid, e.g., benzoic, 2,3 or 4-methylbenzoic, 2,3-, 2,4-, 2,5-,2,6-, 3,4- and 3,5-dimethylbenz0ic, ethylbenzoic,2,4,6-trimethylbenzoic, 2,4,6-triethylbenzoic, anaphthoic,3-methyl-a-naphthoic, an aromatic hydroxyacid, e.g., salicylic acid, anaromatic aminoacid, e.g., paraaminosalicylic, para-aminobenzoic, otheraromatic heterosubstituted acids, e.g., 2,3,4-trimethoxybenzoic,carbamic acids, e.g., carbamic acid, phenylcarbamic, n-butylcarbamic,dimethylcarbamic, diethylcarbamic, allophanic, or a heterocyclic acid,e.g., fi-furyl-carboxylic, N-methylpyrrolidyl-Z-carboxylic, a-picolinic,indole-2-carboxylic, 6-hyand 3-(S-nitro-l-methyl-2-imid-'droxy-indolyl-3-acetic, N methylmorpholyl-Z-carboxylic lysergic,pyrrolyl-2-carboxylic, or other acyl acid.

Examples of R2 are dimethylamino, methyl, ethylamino, diethylaminomethyl, n-propylamino, dipropylamino, diisopropylamino, methyl,isobutylamino, di-n-butylamino, pyrrolidino, 2- methylpyrrolidino, 2,5dimethylpyrrolidino, 3-ethylpyrrolidino, piperidino, homopiperidino,morpholino, imidazole, triazole, tetrazole, oxazole, dioxazole,isothiazole, pyridazine, pyrimidine, piperazine, isoxazine, morpholine,indole, benzoxazine, anilino, N-lower-alkylanilino, benzylamino,N-lower-alkyl-benzylamino, o-toluidino, p-toluidino,N-lower-alkyl-phenylethylamino, etc.

Preferred classes of compounds of this invention are those defined byFormula I wherein:

(a) X=lower-alkyl, i.e., containing 1-4 carbon atoms, or

preferably CH (b) X=18 -hydroxyethyl or esterified-fl-hydroxyethyl,preferably wherein the acyl group thereof is alkanoyl, e.g., of 1-4carbon atoms, or benzoyl; or

(c) R=dialkylamino wherein the alkyl groups are the same and eachcontain 1-5 carbon atoms, preferably diethylamino,

(d) R=dialkylamino as defined above at least one of which alkyl groupscontain a double bond, preferably diallylarnino, or

(e) R=alkyl-thio of l-10 carbon atoms, preferably 38 carbon atoms, or

(f) R=arylamino, e.g., anilino or N-alkylanilino,

(g) R is -S--alkyl,

of 1-6 carbon atoms, e.g., wherein the alkyl group is methyl, ethyl,isopropyl, butyl, amyl, hexyl, etc.

The compounds of this invention can be produced by condensing5-nitro-2-imidazolyl aldehydes with 3-aminooxazolidinones. Others can beproduced by oxidizing a sulfur atom, esterifying a hydroxy group orsaponifying an ester group of the condensation product and/or convertingthe thus-obtained compounds from free base form into the physiologicallycompatible salts thereof, or vice versa.

The condensation of 5-nitro-2-imidazolyl aldehydes with3-amino-oxazolidinones can be conducted in water or an organic solvent,e.g., a lower alcohol, at room temperature or an elevated temperature.In the presence of acids, the reaction takes place more rapidly and witha higher yield. In this case, the corresponding acid addition salts areobtained.

The oxidation of a sulfur atom can be conducted in a conventionalmanner, for example with potassium permanganate or hydrogen peroxide.Saponification of an ester group, esterification of a hydroxy group andconversion into the physiologically acceptable acid addition salt, canbe effected in the conventional manner. Suitable acids for the formationof acid addition salts are, for example: hydrochloric acid, sulfuricacid, acetic acid, lactic acid, succinic acid, and tartaric acid.Preferred acids are those which form physiologically acceptable acidaddition salts. Others can be employed for isolation, purificationand/or characterization purposes.

The novel compounds exhibit good antimicrobial effects, especiallyagainst T richomonas vaginalis, and can thus be employed in thetreatment of Trichomonas vaginalis infections. Table I belowdemonstrates the superior effect of the compounds of this inventionagainst T richomonas vaginalis compared with metronidazole. The,toxicity of the novel compounds is low.

Minimum inhibitroy concentration against Trichomonas vaginalis,Substance 'ylml.

3-(5-nitro-1-methyl-2-irnidazolylmethylenamino)dimethylaminomethyl-Z-oxazolidinone- 0. 403(5-nitro-1-ethyl-2-imidazolylmethylenamino)-5-diethylaminomethyl-2oxazolidinone hydrochloride- 0. 403-(5-nitro-1-butyl-2-imidazolylmethylenamino)-5-diethylaminornethyl-Z-oxazolidinone 0. 403-(5-nitro-1-methy1-2-imidazolylmethylenammo) -5-dibutylaminomethyl-Z-oxazolidinone- 0. 203-(5-nitro-1-methy1-2imidazolylmethylenamino) -5-diallylarninomethy1-2-oxazol1dinone 0.3-(5-nitro-l-methyl-Z-imidazolylmethylenamino) -5-N-methyl-anilinomethyl-2-oxazol1d1none 0. 403-(5-nitro-1-methyl-2-imidazolylrnethylenamino)-5-isopropylthiornethyl-2-oxazol1d1none 0. 053-(5-nitro-1-methyi-2-imidazolylmethylenammo) -5-butylthiomethyl-Z-oxazolidinone 0. 053-(5-nitro-1methyl-2-imidazolylmethylenamlno) -5-hexylthiomethyl-Z-oxazolidinone 0. 403-(5-nitro-1-methyl-2-imidazolylmethylenamino)-5-octylthiomethyl-2oxazolid1none 0. 40 Metronidazole (comparisoncompound) 1. 56

The compounds of Formula I are useful in the treatment of Trich-omonasvaginalis infections. For such use, they can be formulated intoconventional drug forms with the additives, carrier substances, andflavoring agents customary in pharmaceutical preparations which do notdeleteriously react with the effective agents, employing conventionalmethods. For oral application, particularly suitable are tablets,dragees, capsules, pills, suspensions and solutions. Such compositionscan employ, for example, water, alcohol, polyethylene glycols, gelatin,sucrose, lactose, amylose in solutions and suspensions and magnesiumstearate, talc, starch, sugars, etc., in tablets. The concentration ofthe effective agent in the thusformulated compositions is dependent onthe activity of the specific compound employed, the responsiveness ofthe individual patient and the mode of administration. Generally, theycontain about 0.05 to 2.0 g., preferably about 0.05 to 0.5 g. of acompound of this invention and 0.1 to 5 g. of a pharmaceutical carrierper unit dose.

For topical application, the compounds of this invention can be appliedas a powder, solution suspension, foam or aerosol or as vaginal tabletsand suppositories. For parenteral application, aqueous or oily solutionsor suspensions can be used.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE 1 310 mg. of 5-nitro-1-methy1-2-imidazolyl aldehyde and 374 mg.of 3-amino 5 diethylaminomethyl-2-oxazolidinone are boiled in 4 ml. ofethanol with 4 ml. of 12.5N methanolic hydrochloric acid for 1 hour.After cooling, the reaction solution is mixed with a small amount ofisopropyl alcohol and ether. After vacuum-filtering andrecrystallization from isopropyl alcohol-methanol, 310 mg. of3-(5-nitro-1-methyl 2 imidazolyl-methylenamino)- S-diethylaminomethyl 2oxazolidinone is obtained as the hydrochloride, m.p. 233-234 C.

EXAMPLE 2 2.5 g. of 5-nitro 1 methyI-Z-imidazolyl aldehyde and 3 g. of3-amino 5 piperidinomethyl-2-oxazolidinone are boiled in 320 ml. ofalcohol with 1.5 ml. of 12.5N methanolic hydrochloric acid for 2 hours.After cooling and vacuum-filtering, 4 g. of 3-(5-nitro 1methyl-Z-imidazolyl-methylenamino) 5 piperidinomethyl 2 oxazolidinone isobtained as the hydrochloride, m.p. 227- 229 C.

The free base is obtained from this compound by taking up 1 g. of thehydrochloride in 3 ml. of water, mixing with 4N sodium hydroxidesolution until a pH of 10 is attained, and vacuum-filtering. Yield: 600mg., m.p. 171- 173 C.

EXAMPLE 3 414 mg. of S-nitro 1 methyI-Z-imidazolyl aldehyde and 532 mg.of 3-amino 5 piperidinomethyl-Z-oxazolidinone are allowed to stand in 5ml. of ethanol for 5 hours at room temperature. Vacuum-filtering andrecrystallization from ethanol results in 60 mg. of 3-(5- nitro-l-methyl2 imidazolyl-methylenamino) 5 piperidinornethyl-Z-oxazolidinone, m.p.171-173 C.

The hydrochloride is obtained from this product by taking same up inacetone, mixing with methanolic hydrochloric acid, and precipitationwith ether. Yield: 30 mg. from 28 mg. of free base; m.p. 227-229 C.

EXAMPLE 4 310 mg. of 5-nitro 1 methyl 2 imidazolyl aldehyde and 402 mg.of 3-amino-S-morpholinomethyl 2 oxazolidinone are boiled in 6 ml. ofethanol With 2 ml. of 11.8N methanolic hydrochloric acid for 4 hours.Cooling and vacuum-filtering results in 553 mg. of 3-(5-nitro-1- methyl2 imidazolyl-methylenamino) 5 morpholinomethyl-2-oxazolidinone as thehydrochloride, m.p. 214- 215 C.

EXAMPLE 5 5.15 g. of S-nitro 1 methyl-Z-imidazolyl aldehyde and 5.4 g.of 3-amino-5-methylthiomethyl 2 oxazolidinone are boiled in 13 ml. ofmethanol with 13 ml. of 12.5N methanolic hydrochloric acid for twohours. Cooling and vacuum-filtering yields 3.0 g. of 3 (S-nitro-lmethyl2 imidazolyl-methylenamino) 5 methylthiomethyl-2-oxazolidinone, m.p.173-174 C EXAMPLE 7 3.0 g. of S-nitro-l-methyl-Z-imidazolyl aldehyde and3.4 g. of 3-amino-5-ethylthiomethyl-Z-oxazolidinone are treated asdescribed in Example 6. After cooling and mixing the solution withwater, 1.6 g. of 3-(5-nitro-1-methyl- 2 imidazolylmethylenarnino)S-ethylthiomethyl-Z-oxazolidinone is obtained, m.p. -81 C. Afterrecrystallization from methanol, the melting point rises to 129-131 CEXAMPLE 8 1.06 g. of 5 nitro-1-methyl-2-imidazolyl aldehyde and 1.3 g.of 3-amino-5-isopropylthiomethyl-2-oxazolidinone are treated as setforth in Example 7. Yield: 950 mg. of 3 (5nitro-1-methyl-2-imidazoyl-methylenamido-S-isopropylthiomethyl)-2-oxazolidinone,m.p. 148-150 C.

EXAMPLE 9 1.45 g. of S-nitro-1-methyl-2-imidazolyl aldehyde and 2 g. of3 amino 5-butylthiomethyl-oxazolidinone are treated as set out inExample 7. By recrystallizing the reaction product several times frommethanol, 460 mg. of 3(S-nitro-l-methyl-2-imidazolyl-methylenamino)-5-butylthiomethyl2-oxazolidinone is obtained, m.p. 111- 113" C.

7 EXAMPLE 596 mg. of3-(S-nitro-1-methyl-2-imidazolyl-methylenamino)-S-methylthio-2-oxazolidinonein 12 ml. of acetic acid is mixed dropwise with 2 ml. of 30% hydrogenperoxide in such a manner that the temperature remains below 30 C. Afterallowing the reaction mixture to stand for 3 days at room temperature,it is evaporated to dryness under a vacuum; the residue is crystallizedwith water, and the vacuum-filtered precipitate is recrystallized fromacetone-water. Yield: 168 mg. of 3-(5-nitro-1-methyl2-imidazolyl-methylenamino)-5-methylsulfonylmethyl-2-oxazolidinone, m.p.2l6-218 C.

EXAMPLE 1 1 18 g. of 3-dimethylamino-1,2-epoxypropane are added dropwiseto 42 g. of hydrazine hydrate, warmed to 55 C.; during this procedure,the temperature rises to 95 C. After another minutes at 100 C., thereaction mixture is evaporated to dryness and distilled, thus obtaining17.3 g. of 1 hydrazine-3-dimethylamino-2-propanol, b.p. 91 95 C. at 0.05mm. Hg. This product is added dropwise, together with 16.9 g. of diethylcarbonate, to a solution of 480 mg. of sodium in 21 ml. of absolutemethanol. The mixture is then boiled for one hour, and 29 ml. of solventare gradually distilled off under normal pressure. The residue of g. of3 amino-S-dimethylaminomethyl-2- oxazolidinone crystallizes duringdrying under a vacuum. 159 mg. of this compound is boiled for two hourswith 155 mg. of 5-nitro-1-methyl-2-imidazolyl aldehyde in 3 ml. ofethanol with 0.096 ml. of 12.5N HCl. By cooling and vacuum-filtering, 63mg. of 3-(6-nitro-1-methyl-2- imidazolyl-methylenamino) 5dimethylaminomethyl-Z- oxazolidinone hydrochloride is obtained, m.p. 251C.

By stirring 159 mg. of 3-amino-S-dimethylaminomethyl-2-oxazolidinonewith 155 mg. of aldehyde in 1.5 ml. of water and 1.25 ml. of 1Nhydrochloric acid for three hours at room temperature, and thenrendering the reaction mixture alkaline with 1N potassium hydroxide, 73mg. of the corresponding free base is obtained, m.p.

EXAMPLE 12 11 g. (78 millimols) of 5 nitro-l-ethyl-imidazole is heatedwith 11.7 g. of paraformaldehyde in 57 ml. of dimethyl sulfoxide for 48hours at 110 C. in a sealed tube. After distilling off the volatilecomponents at 1 mm. Hg and 100 C. bath temperature, the residue isrecrystallized twice from benzene, thus obtaining 5.1 g. of 5-nitro-1-ethyl-2-hydroxymethylimidazole, m.p. 101 C. 3.42 g. of this compoundis boiled for 8 hours in 13 ml. of benzene with 15 g. oflead-IV-acetate. The benzenic solution is cooled, filtered, washedneutral, and dried. After evaporation under a vacuum, 2.37 g. of5-nitro-1-ethyl-2-imidazolyl aldehyde is obtained in the form of an oil.

2.08 g. of this aldehyde is boiled for two hours in 36 ml. of ethanolwith 2.25 g. of 3-amino-5-diethylaminomethyl-2-oxazolidinone and 1.15ml. of 12.5N methanolic hydrochloric acid. After mixing with twice thevolume of isopropanol, the reaction mixture is cooled andvacuum-filtered, thus obtaining 1.6 g. of 3-(5-nitro-1-ethyl-2-imidazolyl-methylenamino)-5-diethylaminomethyl-2-oxazolidinonehydrochloride, m.p. 176 C.

EXAMPLE 13 4.0 g. of 5-nitro-1-butyl-2-hydroxymethyl-imidazole istreated with lead-IV-acetate and worked up as described in Example 12,thus obtaining 3.03 g. of 5-nitro-1-butyl- 2-imidazolyl aldehyde as anoil. 610 mg. of this aldehyde is boiled for two hours in 10 ml. ofethanol with 580 mg. of 3 amino-S-diethyl-aminomethyl-Z-oxazolidinoneand 0.3 ml. of 12.5N methanolic hydrochloric acid. By concentration andpreparative layer chromatography with methanol-chloroform, 1:1, 342 mg.of 3-(5-nitro-1-butyl- 2 imidazolyl-methylenamino)S-diethylaminomethyl-Z- oxazolidinone is obtained as the free base, m.p.79 C.

8 EXAMPLE 14 2.84 g. of 5-nitro-1-(Z-acetoxyethyl)-2-imidazolyl aldehydeis boiled for two hours in 40 ml. of ethanol with 2.34 g. of3-amino-S-diethylaminomethyl-2-oxazolidinone and 1 ml. of 12.5Nmethanolic hydrochloric acid. Cooling and vacuum-filtering results in3.3 g. of 3-[5-nitro-1-(2- acetoxyethyl) 2imidazolyl-methylenamino]-5-diethylaminomethyl 2 oxazolidinonehydrochloride, m.p. 203 C.

EXAMPLE 15 2.7 g. of 3[5-nitro-1-(2-acetoxyethyl)-2-imidazolylmethylenamino]5-diethylaminomethyl-2-oxazolidinone hydrochloride is boiled for threehours in ml. of ethanol with 0.15 ml. of 12.5N methanolic hydrochloricacid. Cooling and vacuum-filtering results in 2.08 g. of 3-[5- nitro 1-Z-hydroxyethyl -Z-imidazolyl-methylenamino 5 diethylaminomethyl2-oxazolidinone hydrochloride, m.p. 175 C.

EXAMPLE 16 155 mg. of 5-nitro-1-methyl-2-imidazolyl aldehyde and 242 mg.of 3-amino-5-dibutylaminomethyl-2-oxazolidinone are boiled for fourhours in 3 ml. of ethanol with 0.096 ml. of 12.5N methanolichydrochloric acid. Cooling and vacuum-filtering results in 53 mg. of3-(5-nitro-1- methyl 2imidazolyl-methylenamino)-5-dibutylaminomethyl-Z-oxazolidinone,remarkably in the form of the free base, m.p. 136 C.

EXAMPLE 17 155 mg. of 5-nitro-1-methyl-2-imidazolyl aldehyde and 211 mg.of 3-amino-S-diallylaminomethyl-2-oxazolidinone are stirred for 3 hoursin 1.5 ml. of water and 1.5 ml. of 1N hydrochloric acid. By renderingthe reacting mixture alkaline with 1N potassium hydroxide, a precipitateis obtained of 210 mg. of 3(S-nitro-1-rnethyl-2-imidaz0lylmethylenamino) 5diallylaminomethyl-Z-oxazolidinone, m.p. 157 C.

EXAMPLE 18 32.6 g. of 3-N-methylanilino 1,2 epoxypropane are addeddropwise to 46.6 g. of hydrazine hydrate warmed to 55 C. During thisprocedure, the temperature rises to C. After another 15 minutes at C.,the reaction mixture is concentrated under a vacuum. 1.95 g. of thethus-obtained crude l-hydrazino 3 N methylanilino- 2-propanol is addeddropwise with 1.3 g. of diethyl carbonate to a solution of 37 mg. ofsodium in 1.6 ml. of methanol. The reaction mixture is gradually heatedto a bath temperature of C., and within one hour 2 ml. of solvent isdistilled off under normal pressure. 221 mg. of the crude 3-amino 5 Nmethylanilinomethyl 2- oxazolidinone obtained in this manner is boiledfor two hours with mg. of S-nitro-l-methyl-Z-imidazolyl aldehyde in 3ml. of ethanol and 0.096 ml. of 12.5 N methanolic hydrochloric acid.Cooling and vacuum-filtering results in 84 mg. of 3-(5-nitro-1-methyl 2imidazolylmethylenamino)-5-N-methylanilinomethyl 2 oxazolidinone, m.p.233 C.

By stirring the same amounts of starting compounds in 3 ml. of 0.5 Nhydrochloric acid, 205 mg. of the same compound is obtained after twoand one-half hours, as a precipitate.

EXAMPLE 19 12.0 g. of 3-hexylmercapto-1,2-epoxypropane are addeddropwise at 90 C., to 17 g. of hydrazine hydrate; during this step, thetemperature rises to 110 C. After another two hours at 100 C., thereaction mixture is concentrated by evaporation under a vacuum, thusobtaining 13.9 g. of 1 hydrazine 3 hexylmercapto 2- propanol as acrystalline residue, m.p. 45-50 C. 5.0 g. of this compound is added in 4ml. of methanol with 2.8 g. of diethyl carbonate to a solution of 28 mg.of sodium in 1 ml. of methanol. Within one hour, 6 ml. of solvent isdistilled off under normal pressure. The yield in crude 3-amino-5hexylmercaptomethyl 2 oxazolidinone is 5.3 g. 500 mg. of this compoundis boiled for one hour in 1.2 ml. of methanol with 333 mg. ofS-ni'tro-l-methyl-2- imidazolyl aldehyde. By cooling, mixing with 20 ml.of water, and vacuum-filtering, and after recrystallization frommethanol, 121 mg. of 3-(5 nitro 1 methyl-2- imidazolyl-methyl-enamino)hexylmercaptomethyl- 2-oxazolidinone is obtained, m.p. 117 C.

EXAMPLE 20 50.5 g. of diisopropylamine is added to 47 g. ofepich'lorhydrin and 1 ml. of water, at 20 C. After allowing the reactionmixture to stand for eight hours at 50 C.,

it is cooled to 20-25 C., and at this temperature, 24 g. f sodiumhydroxide in 40 ml. of water is added dropwise. After stirring themixture for one hour, 100- ml. of water is added until the thus-formedsodium chloride is dissolved. The upper organic layer is separated, andthe aqueous phase is shaken out with ether three times. The combinedorganic phases are dried over potassium hydroxide, filtered, and thesolvent is removed under a vacuum. By distilling the residue under 13mm. Hg, at 70- 81 C., 15.1 g. of 1-diisopropylan1ino-2,3-epoxypropane isobtained.

15.1 g. of this substance is added dropwise to 100% hydrazine hydrate,warmed to 55 C., under agitation. Then, the reaction mixture isgradually heated to 100 C. and stirred for 30 minutes at thistemperature. Any excess hydrazine hydrate is removed under a vacuum,thus obtaining 16.0 g. of crude 1 diisopropylarnino 3-hydrazino-Z-propanol. 16.0 g. of this substance is added dropwise with11.2 g. of diethyl carbonate to a solution of 310 mg. of sodium in 13.5ml. of absolute methanol. Thereafter, the reaction mixture is heatedwithin one hour to 110 C. (bath temperature), and within 1-2 hours, thesolvents are distilled off under normal pressure. 18.4 g. of crude3-amino-S-diisopropylaminomethyl 2 oxazolidinone is obtained as theresidue.

215 mg. of this substance is stirred at room temperature with 155 mg. ofS-nitro-l-methyl-Z-imidazolyl aldehyde in 1.5 ml. of water and 1.25 ml.of 2N hydrochloric acid. Then, the reaction mixture is rendered alkalinewith 1N potassium hydroxide solution, and vacuum-filtered. Theprecipitate is recrystallized from methanol, thus obtaining 175 mg. of3-(5-nitro-1 methyl 2imidazolylmethylenamino)-S-diisopropylaminomethyl-2 oxazolidinone, m.p.205206 C.

EXAMPLE 21 Epichlorohydrin and di-n-propylamine result, as described inExample 20, in l-di-n-propylamino-2,3-epoxy propane, but the reactiontakes place more spontaneously, and must be maintained at 40-45 C. bycooling. Yield: 17%; boiling point at 13 mm. Hg: 70-71 C. Then, asdescribed in Example 20, l-di-n-propylamino 3 hydrazino-2-propanol(crude) is obtained with hydrazine hydrate, at a yield of 92%. From thisproduct, with diethyl carbonate, 3-amino 5 di n propylaminomethyl-Z-oxazolidinone (crude) is obtained with a 92% yield, and therefrom, with5-nitro-l-methyl-2-imid.azolyl aldehyde, 3-(5-nitro-1-methyl-2imidazolyl methylenamino) 5- di-n-propylaminomethyl 2 oxazolidinone isproduced, m.p. 169-170" C. (from methanolisopropanol) with a yield of55%.

EXAMPLE 22 Epichlorohydrin and diisoamylamine result, as described inExample 20, in l-diisoamylamino 2,3 epoxypropane; yield: 38%, boilingpoint at 12 mm. Hg: 115- 117 C.

As described in Example 20, 1 diisoamylamino 3- hydrazino-Z-propanol(crude) is obtained therefrom with hydrazine hydrate (but at 160 C.), ata yield of 70%; from this product, with diethyl carbonate,3-amino-5-diisoamylaminomethyl2-oxazolidinone (crude) is obtained at ayield of 82%, and from this compound, with S-nitrol-methyl-2-imidazolylaldehyde, 3-(5 nitro 1 methyl- Z-imid-azolyl-methylenamino)-5diisoamylaminomethyl- 2-oxazolidinone is obtained, m.p. 122-125 C. witha yield of 20%; this product crystallizes from the hydrochloric acidsolution in the form of the free base.

EXAMPLE 23 Epichlorohydrin and 4-methylpiperidine result, as describedin Example 21, in 1 (4 methylpiperidino)-2,3- epoxypropane. Yield: 50%b.p. at 13 mm. Hg: 89- 92 C.

As described in Example 20, there is produced therefrom, with hydrazinehydrate, l-(4-methylpiperidino)-3- hydrazino-Z-propanol (crude) with ayield of and from this product, with diethyl carbonate, 3-amino-5 (4-methylpiperidinomethyl) 2 oxazolidinone is obtained (recrystallizedtwice from isopropanol), at a yield of 23%.

2.76 g. of this substance and 2.0 g. of S-nitro-I-methyl- 2-imidazolylaldehyde are boiled for two hours in 36 ml. of absolute ethanol with1.16 ml. of 12.5N methanolic hydrochloric acid. After cooling,vacuum-filtering, and recrystallization from methanol, 3-(5-nitro 1methyl-2- imidazolyl-methylenamino) 5 (4 methylpiperidinomethyl) 2oxazolidinone hydrochloride is obtained at a yield of 63% and a meltingpoint of 229230 C.

EXAMPLE 24 As described in Example 20, 3-amino 5 pyrrolidinomethyl 2oxazolidinone (crude) is obtained with a 70% yield from crudel-pyrrolidino 3 hydrazino-2-propanol and diethyl carbonate. 185 mg. ofthis substance and 155 mg. of S-nitro 1 methyl 2 imidazolyl aldehyde areboiled for two hours in 3 ml. of absolute methanol with 0.1 ml. of 12.5Nmethanolic hydrochloric acid. After cooling, mixing with isopropanol,and recrystallization of the thus-produced precipitate from isopropanol,3 (5- nitro 1 methyl 2 imidazolyl-methylenamino)-5-pyrrolidinomethyl 2oxazolidinone hydrochloride is obtained. Yield: 41 mg., m.p. 220-222 C.

EXAMPLE 25 As described in Example 20, 1-hexamethylenimino-3- hydrazine2 propanol (crude) is obtained at an 83% yield from hexamethylenimineand hydrazine hydrate, and from this product with diethyl carbonate,3-amino-5-hexamethyleniminomethyl 2 oxazolidinone (crude) is producedwith a yield of 2.56 g. of this substance is boiled for two hours with1.86 g. of S-nitro 1 methyl 2 imidazolyl aldehyde in 34 ml. of ethanoland 1.08 ml. of 12.5N methanolic hydrochloric acid. After cooling,vacuum-filtering and recrystallization from methanol, 610 mg. of3-(5-nitro-1- methyl-2-imidazolyl-methylenamino) 5 hexamethyleniminomethyl 2 oxazolidinone is obtained as the free base, m.p. 163-165C. Hydrochloride: m.p. 235238 C.

EXAMPLE 26 390 mg. of 3-[5-nitro 1 (2-hydroxyethyl)-2-imidazo1-yl-methylenamino] 5 diethylaminomethyl 2 oxazolidinone hydrochloride ismixed in 4 ml. of pyridine with 1 ml. of dimethylformamide and 0.23 ml.of benzoyl chloride. After allowing the reaction mixture to stand for 24hours at room temperature and for 1 hour at 50 C., it is poured into 60ml. of ice water. The reaction product is vacuum-filtered from thethus-produced benzoic acid; the filtrate is washed with ethyl acetateand made alkaline with sodium hydroxide solution. The thus-producedprecipitate is vacuum-filtered and recrystallized from ethanol, thusobtaining 40 mg. of 3-[5-nitro 1 (2-benzoyloxyethyl) 2imidazolyl-methylenamino] 5 diethylaminomethyl-Z-oxazolidinone, m.p.168170 C 1 1 EXAMPLE 27 23 g. of epichlorohydrin and 41 g. ofl-octanethiol are mixed, under boiling heat, with 0.5 g. of zincchloride. A violent exothermic reaction is thus initiated. Afterstirring the reaction mixture for one hour at 120 C., it is subjected todistillation, thus obtaining 32 g. of 1-chloro- 3-octanethio 2 propanol,b.p. 126-136 C. at 0.2 mm. Hg. Refractive index: n =1.483O. 27 g. ofthis substance is mixed with 31 g. of potassium hydroxide in 40 ml. ofwater in such a manner that the temperature remains between and C. Aftertwo hours at room temperature, the reaction mixture is extracted withether, the ether phases are dried, filtered, and concentrated under avacuum. By distilling the residue, 8.6 g. of l-octanethio- 2,3epoxypropane is obtained, b.p. 78-81 C. at 0.05 mm. Hg of pressure.Index of refraction: n =1.4706. The entire amount of substance is addeddropwise at 90 C. to 10.5 g. of 98% hydrazine hydrate. After a furthertwo hours at 100 C., the excess hydrazine hydrate is removed under avacuum, thus obtaining 9.9 g. of 1-octanethio-3- hydrazino 2 propanol asa crystalline-hygroscopic residue. This substance is treated withdiethyl carbonate, as described in Example 20, and yields 3-arnino 5octylthiomethyl-2-oxazolidinone (crude) with a yield of 80%.

560 mg. of this substance is boiled for one hour With 333 mg. of S-nitro1 methyl 2 imidazolyl aldehyde in 1.2 ml. of absolute methanol and 0.2ml. of 12.5N methanolic hyldrochloric acid. After cooling, the reactionmixture is mixed with a small amount of water, vacuumfiltered, and theprecipitate recrystallized twice from methanol-water, thus obtaining 152mg. of 3-(5-nitro-1-methyl- 2 imidazolyl-methylenamino) 5octylthi0methyl-2- oxazolidinone, m.p. 10l103 C.

EXAMPLE 28 To a solution of 120 mg. of sodium in 4 ml. of absolutemethanol, 11.8 g. of diethyl carbonate is added, and to this mixture isfurther added 16.8 g. of l-methylsulfonyl- 3-hydrazino 2 propanol. Thereaction mixture is gradually heated to 110 C., and during this process,solvent is distilled off. The residue is diluted with ml. of ethanol,and 10 ml. of 12.5N methanolic hydrochloric acid is added thereto, asWell as 15.5 g. of 5-nitro 1 methyl-Z-imidazolyl aldehyde. After boilingfor one hour, the reaction mixture is cooled and diluted with a smallamount of Water. By recrystallization of the vacuum-filtered precipitatefrom acetone/ water, 7 g. of 3-(5-nitro-1-methyl- 2imidazolyl-methylenamino) 5 methylsulfonylmethyl-2-oxazolidinone isproduced, m.p. 216218 C.

EXAMPLE 29 2 g. of 5 nitro 1 (2 benzoyloxyethyl)imidazole, 1.15 g. ofparaformaldehyde, and 7 ml. of dimethyl sulfoxide are treated for 24hours in a bomb tube at 110 C. The residue obtained after removal of thesolvent is extracted with benzene. From the benzene crystallizes 345 mg.of S-nitro 2 hydroxymethyl 1 (Z-benzoyloxyethyl)-imidazole, m.p. 136139C. 264 mg. of this substance is boiled for eight hours in 5 ml. ofbenzene with 656 mg. of lead-IV-acetate. After vacuum-filtering, mixingthe filtrate with water, washing it neutral, and concentrating theorganic phase, 224 mg. of 5-nitro-1-(2- benzoyloxyethyl) 2 imidazolylaldehyde is obtained, m.p. 113l14 C.

145 mg. of this compound is boiled for one hour With 93 mg. of 3 amino 5diethylaminomethyl-2-oxazolidinone in 4 ml. of alcohol with 0.05 ml. of12.5N methanolic hydrochloric acid. After cooling, vacuum-filtering,taking up the precipitate in methanol-water, and mixing the solutionwith aqueous solution of sodium hydroxide, mg. of 3-[5-nitro 1(Z-benzoyloxyethyl)-2-imidazolyl-methylenamino] 5 diethylaminomethyl 2oxazolidinone is obtained, m.p. 168170 C.

12 EXAMPLE A 250 mg. of3-(S-nitro-l-methyl-2-imidazolyl-methylenamino)-5-morpholinomethyl-2-oxazolidinonehydrochloride was filled into gelatin capsules for oral therapy.

EXAMPLE B 250 mg. of3-(S-nitro-1-methyl-2-imidazolyl-methylenamino)-5-morpholinomethyl-2-oxazolidinonehydrochloride was filled into gelatin capsules coated with Eldragitlacquer and thus resistant to stomach acid, for oral therapy.

EXAMPLE C 250 g. of3-(5-nitro-1-methyl-2-imidazolyl-methylenamino)-5-morpholinomethyl-2oxazolidinone hydrochloride, 150 g. of lactose, g. of corn starch, 12 g.of polyvinylpyrrolidone, 1 g. of magnesium stearate and 7 g. of talcwere mixed homogeneously and pressed, in a conventional tableting press,into 520 mg. tablets adapted for oral administration, each tabletcontaining 250 mg. of effective agent.

EXAMPLE D 50 g. of3-(5-nitro-1-methyl-2-imidazolyl-methylenamino)-5-morpholinomethyl-2oxazolidinone hydrochloride, 508 g. of lactose, 200 g. of Avicel PH 101,40 g. of corn starch and 2 g. of magnesium stearate were mixedhomogeneously and formed in a tableting press into vaginal tablets of800 mg, each containing 50 mg. of effective agent.

EXAMPLE -E g. of3-(S-nitro-1-methyl-2-imidazolyl-methylenamino)-5-di-n-propylaminomethyl-Zoxazolidinone, 150 g. of lactose, 100 g. of corn starch, 12 g. ofpolyvinylpyrrolidone, 1 g. of magnesium stearate and 7 g. of talc weremixed homogeneously and pressed, in a tableting press, into tablets of420 mg. each adapted for oral administration, each containing 150 mg. ofeffective agent.

Following the procedures of Examples A to E, each of the compounds ofExamples 1-29 can be formulated into a corresponding pharmaceuticalcomposition adapted for oral or vaginal administration.

EXAMPLE F To a premenopausal mature female patient infected withTrichomonas vaginalis, administer twice daily orally a 250 mg. gelatincapsule of Example A. Continue this daily medication for at least 6days, until vaginal cultures of the patient are negative.

EXAMPLE G Follow the procedure of Example E, except administer vaginallythe tablets of Example D once daily.

The preceding examples can be repeated with similar success bysubstituting the generically and specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:

1. A pharmaceutical composition containing, in admixture with apharmaceutically acceptable carrier, a trichomonacidally effectiveamount of a 3-(5-nitro-2- imidazolylmethylenamino) 2 oxazolidinone ofthe formula I C X ll 0 wherein X is alkyl or alkenyl of 1-5 carbon atomsor alkyl of 25 carbon atoms substituted at the 2-position by hydroxy,alkanoyloxy of 1-5 carbon atoms or benzoyloxy; and R is SA, SO A orwherein A is alkyl of 1-10 carbon atoms and R and R each are alkyl of1-5 carbon atoms, phenyl or benzyl or, collectively with the N-atom apyrrolidino, piperidino, homopiperidino, morpholino, piperazino or acorresponding ring substituted by alkyl of lcarbon atoms, or aphysiologically acceptable acid addition salt thereof.

2. A composition of Claim 1 wherein X is lower-alkyl.

3. A composition of Claim 2 wherein X is methyl.

4. A composition of Claim 1 wherein R is dialkylamino each alkyl ofwhich contains 1-5 carbon atoms.

5. A composition of Claim 4 wherein R is di-n-propylamino.

6. A composition of Claim 1 wherein R is morpholino.

7. A composition according to Claim 1 wherein the oxazolidinone is3-(5-nitro-1 methyl 2 imidazolylmethylenamino) 5 morpholinomethyl-2-oxazolidinone hydrochloride.

8. A composition according to Claim 1 wherein the oxazolidin'one is 3 (5nitro-l-methyl-Z-imidazolylmethylenamino) 5-di-n-propylaminomethyl-Z-oxazolidinone.

9. A composition according to Claim 1 containing about 0.05 to 2.0 g. ofthe oxazolidinone per unit dosage.

10. A composition according to Claim 1 adapted for oral ingestion.

11. A composition according to Claim 7 adapted for oral ingestion.

12. A composition according to Claim 8 adapted for oral ingestion.

13. A process for the treatment of trichomoniasis which comprisesadministering to the infected patient a trichomonacid-ally effectiveamount of a compound of the formula wherein X is alkyl or alkenyl of 1-5carbon atoms or alkyl of 2-5 carbon atoms substituted at the 2-positionby hydroxy, alkanoyloxy of 1-5 carbon atoms or benzoyloxy; and R is SA,SO -A or wherein A is alkyl of 1-10 carbon atoms and R and R each arealkyl of 1-5 carbon atoms, phenyl or benzyl or, collectively with theN-atom, a pyrrolidino, piperidino, homopiperidino, morpholino,piperazino or a corresponding ring substituted by alkyl of 1-5 carbonatoms, or a physiologically acceptable acid addition salt thereof.

14. A process according to Claim 13 wherein X is lower-alkyl.

15. A process according to Claim 14 wherein X is methyl.

16. A process according to Claim 13 wherein R is dialkylamino each alkyl01: which contains 1-5 carbon atoms.

17. A process according to Claim 16 wherein R is di-npropylamino.

18. A process according to Claim 13 wherein R is morpholino.

19. A process according to Claim 13 wherein the oxazolidinone is3-(5-nitro-1-methyl-2 imidazolylmethylenamino)-5-morpholinornethyl 2oxazolidinone hydrochloride.

20. A process according to Claim 13 wherein the oxazolidinone is3-(5-nitro-1-methyl 2imidazolylmethylenamino)-5-di-n-propylaminomethyl-2 oxazolidinone.

21. A process according to Claim 13 wherein the administration is oral.

22. A process according to Claim 19 wherein the administration is oral.

23. A process according to Claim 20 wherein the administration is oral.

References Cited UNITED STATES PATENTS 3,272,828 9/ 1966 Vow Esch260-295 3,288,787 11/1966 Massaroli 260-240 3,318,878 5/1967 Dunn260-240 3,452,035 6/ 1969 Bevkelhammeu et al.

FOREIGN PATENTS 17,585 8/1963 Japan 260-240 I'EROME D. GOLDBERG, PrimaryExaminer US. Cl. X.R.

:I I NITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION.

paten No, 3,839,567 Dated Oetober 1, 1974- Ioyentor(s) Clemens Rufer, eta1.

It is ceftiiied that error appears in the above-identified patent andthat said Letters Patent are hereby correoted as shown below:

IN THE.HEAD#NG, COLfiMN 1: The Aseignee of Record, ScheringAktieageseiieehaft,

should reao fe Berlin and Bergkamen, Federal Republic of Germany 1Signed and sealed this 31st day of December 1974,

(SEAL) Attest:

MCCOY M. GIBSON c. MARSHALL DANN Attesting Officer v Commissioner ofPatents FORM PO-1050*(10-69) USCOMWDC 6037M,

* U.$ GOVERNMENT PRINTING OFFICE l9! 0-366-334,

1. A PHARMACEUTICAL COMPOSITION CONTAINING, IN ADMIXTURE WITH APHARMACEUTICALLY ACCEPTABLE CARRIER, A TRICHOMONACIDALLY EFFECTIVEAMOUNT OF A 3-(5-NITRO-2IMIDAZOLYLMETHYLENAMINO) - 2 - OXAZOLIDINONE OFTHE FORMULA